Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2.

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Hatzenbuhler NT, Baudy R, Evrard DA, Failli A, Harrison BL, Lenicek S, Mewshaw RE, Saab A, Shah U, Sze J, Zhang M, Zhou D, Chlenov M, Kagan M, Golembieski J, Hornby G, Lai M, Smith DL, Sullivan KM, Schechter LE, Andree TH

Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2.

J Med Chem. 2008 Nov 13;51(21):6980-7004. doi: 10.1021/jm8007097. Epub 2008 Oct 4.

PubMed ID
18834188 [ View in PubMed
]
Abstract

Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
FluoxetineSodium-dependent serotonin transporterIC 50 (nM)39.4N/AN/ADetails